Sapropterin Drug Information

Sapropterin dihydrochloride tablets are indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Sapropterin dihydrochloride tablets are to be used in conjunction with a Phe-restricted diet. Sapropterin dihydrochloride tablets are a phenylalanine hydroxylase activator indicated to reduce blood phenylalanine (Phe) levels in adult and pediatric patients one month of age and older with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive Phenylketonuria (PKU). Sapropterin dihydrochloride tablets are to be used in conjunction with a Phe-restricted diet.

Recommendations

Prior to Sapropterin Dihydrochloride Tablets Treatment Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.

Recommended Dosage and

Administration The recommended starting dosage of sapropterin dihydrochloride tablets are: Pediatric Patients 1 month to 6 years: 10 mg/kg (actual body weight) administered orally once daily. Patients 7 years and older: 10 to 20 mg/kg (actual body weight) administered orally once daily. Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day.

A missed dose should be administered as soon as possible, but two doses should not be administered on the same day. Evaluation Period Existing dietary protein and Phe intake should not be modified during the evaluation period. If a 10 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 10 mg/kg per day for a period of up to 1 month.

Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride tablets treatment and periodically for up to a month. If blood Phe does not decrease from baseline at 10 mg/kg per day, the dose may be increased to 20 mg/kg per day. Patients whose blood Phe does not decrease after 1 month of treatment at 20 mg/kg per day do not show a biochemical response and treatment with sapropterin dihydrochloride tablets should be discontinued in these patients.

If a 20 mg/kg per day starting dose is used, then response to therapy is determined by change in blood Phe following treatment with sapropterin dihydrochloride tablets at 20 mg/kg per day for a period of 1 month. Blood Phe levels should be checked after 1 week of sapropterin dihydrochloride tablets treatment and periodically during the first month. Treatment should be discontinued in patients who do not show a biochemical response (blood Phe does not decrease) after 1 month of treatment at 20 mg/kg per day.

Dosage Adjustment Once responsiveness to sapropterin dihydrochloride tablets has been established, the dosage may be adjusted within the range of 5 to 20 mg/kg per day according to biochemical response to therapy (blood Phe). Periodic blood Phe monitoring is recommended to assess blood Phe control, especially in pediatric patients .

Preparation and

Administration Instructions Sapropterin dihydrochloride tablets may be swallowed either as whole tablets or dissolved in 120 to 240 mL of water or apple juice and taken orally within 15 minutes of dissolution. It may take a few minutes for the tablets to dissolve. To make the tablets dissolve faster, tablets may be stirred or crushed.

The tablets may not dissolve completely. Patients may see small pieces floating on top of the water or apple juice. This is normal and safe for patients to swallow.

If after drinking the medicine, patients still see pieces of the tablet in the container, more water or apple juice can be added to make sure all of the medicine is consumed. Sapropterin dihydrochloride tablets may also be crushed and then mixed in a small amount of soft foods such as apple sauce or pudding.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. PKU Clinical Studies The safety of sapropterin dihydrochloride was evaluated in 7 clinical studies in patients with PKU (aged 1 month to 50 years) . In Studies 1 to 4 (controlled and uncontrolled studies), 579 patients with PKU aged 4 to 49 years received sapropterin dihydrochloride in doses ranging from 5 to 20 mg/kg per day for lengths of treatment ranging from 1 to 164 weeks. The patient population was evenly distributed in gender, and approximately 95% of patients were Caucasian.

The most common adverse reactions (≥4% of patients) were headache, rhinorrhea, pharyngolaryngeal pain, diarrhea, vomiting, cough, and nasal congestion. The data described in Table 3 reflect exposure of 74 patients with PKU to sapropterin dihydrochloride at doses of 10 to 20 mg/kg per day for 6 to 10 weeks in two double-blind, placebo-controlled clinical trials (Studies 2 and 4). Table 3 enumerates adverse reactions occurring in at least 4% of patients treated with sapropterin dihydrochloride in the double-blind, placebo-controlled clinical trials described above. Table 3: Summary of Adverse Reactions Occurring in ≥4% of Patients in Placebo-Controlled Clinical Studies with Sapropterin Dihydrochloride MedDRA Preferred Term Treatment Sapropterin dihydrochloride (N=74) Placebo (N=59) No.

Patients (%) No. Patients (%) Headache 11 8 Rhinorrhea 8 0 Pharyngolaryngeal pain 7 1 Diarrhea 6 3 Vomiting 6 4 Cough 5 3 Nasal congestion 3 0 In open-label, uncontrolled clinical trials (Studies 1 and 3) all patients received sapropterin dihydrochloride in doses of 5 to 20 mg/kg per day, and adverse reactions were similar in type and frequency to those reported in the double-blind, placebo-controlled clinical trials . In Study 5, 65 pediatric patients with PKU aged 1 month to 6 years received sapropterin dihydrochloride 20 mg/kg per day for 6 months. Adverse reactions in these patients were similar in frequency and type as those seen in other sapropterin dihydrochloride clinical trials except for an increased incidence of low Phe levels.

Twenty-five percent (16 out of 65) of patients developed Phe levels below normal for age . In Study 6, a long term, open-label, extension study of 111 patients aged 4 to 50 years, receiving sapropterin dihydrochloride in doses ranging from 5 to 20 mg/kg per day, adverse reactions were similar in type and frequency to those reported in the previous clinical studies. Fifty-five patients received sapropterin dihydrochloride both as dissolved and intact tablets. There were no notable differences in the incidence or severity of adverse reactions between the two methods of administration.

The mean (± SD) exposure to sapropterin for the entire study population was 659 ± 221 days (maximum 953 days). In Study 7, 27 pediatric patients with PKU aged 0 to 4 years received sapropterin dihydrochloride 10 mg/kg per day or 20 mg/kg per day. Adverse reactions were similar in type and frequency to those observed in other clinical trials, with the addition of rhinitis, which was reported in 2 subjects (7.4%). Safety Experience from Clinical Studies for Non-PKU Indications Approximately 800 healthy subjects and patients with disorders other than PKU, some of whom had underlying neurologic disorders or cardiovascular disease, have been administered a different formulation of the same active ingredient (sapropterin) in approximately 19 controlled and uncontrolled clinical trials. In these clinical trials, subjects were administered sapropterin at doses ranging from 1 to 100 mg/kg per day for lengths of exposure from 1 day to 2 years.

Serious and severe adverse reactions (regardless of causality) during sapropterin administration were seizures, exacerbation of seizures , dizziness, gastrointestinal bleeding, post-procedural bleeding, headache, irritability, myocardial infarction, overstimulation, and respiratory failure. Common adverse reactions were headache, peripheral edema, arthralgia, polyuria, agitation, dizziness, nausea, pharyngitis, abdominal pain, upper abdominal pain, and upper respiratory tract infection.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of sapropterin dihydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions including anaphylaxis and rash : Most hypersensitivity reactions occurred within several days of initiating treatment.

Gastrointestinal reactions : esophagitis, gastritis, oropharyngeal pain, pharyngitis, esophageal pain, abdominal pain, dyspepsia, nausea, and vomiting . Hyperactivity : Two cases have been reported. In one case, the patient received an accidental overdosage of sapropterin dihydrochloride.

Table 4 includes drugs with clinically important drug interactions when administered with sapropterin dihydrochloride and instructions for preventing or managing them. Table 4: Clinically Relevant Drug Interactions Levodopa Clinical Impact Sapropterin dihydrochloride may increase the availability of tyrosine, a precursor of levodopa. Neurologic events were reported postmarketing in patients receiving sapropterin and levodopa concomitantly for a non- PKU indication.

Intervention Monitor patients for a change in neurologic status. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) Clinical Impact In vitro and in vivo nonclinical data suggest that drugs that inhibit folate synthesis may decrease the bioavailability of endogenous BH4 by inhibiting the enzyme dihydrofolate reductase, which is involved in the recycling (regeneration) of BH4. This reduction in net BH4 levels may increase Phe levels. Intervention Consider monitoring blood Phe levels more frequently during concomitant administration.

An increased dosage of sapropterin dihydrochloride may be necessary to achieve a biochemical response. Drugs Affecting Nitric Oxide-Mediated Vasorelaxation (e.g., PDE-5 inhibitors such as sildenafil, vardenafil, or tadalafil) Clinical Impact Both sapropterin dihydrochloride and PDE-5 inhibitors may induce vasorelaxation. A reduction in blood pressure could occur; however, the combined use of these medications has not been evaluated in humans.

Intervention Monitor blood pressure. Inhibitors of Folate Synthesis (e.g., methotrexate, valproic acid, phenobarbital, trimethoprim) : Can decrease endogenous BH4 levels; monitor blood Phe levels more frequently and adjust sapropterin dihydrochloride dosage as needed. Drugs Affecting Nitric Oxide-Mediated Vasorelaxation (e.g., PDE-5 inhibitors) : Potential for vasorelaxation; monitor blood pressure.

Pregnancy Risk Summary Available data from pregnancy safety studies, pharmacovigilance, and published case reports with sapropterin dihydrochloride use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects (see Clinical Considerations). An embryo-fetal development study with sapropterin dihydrochloride in rats using oral doses up to 3 times the maximum recommended human dose (MRHD) given during the period of organogenesis showed no effects. In a rabbit study using oral administration of sapropterin dihydrochloride during the period of organogenesis, a rare defect, holoprosencephaly, was noted at 10 times the MRHD. All pregnancies have a background risk of major birth defects, pregnancy loss, or other adverse pregnancy outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

The estimated background risk of major birth defects and miscarriage in pregnant women with PKU who maintain blood phenylalanine concentrations greater than 600 micromol/L during pregnancy is greater than the corresponding background risk for pregnant women without PKU. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Uncontrolled blood phenylalanine concentrations before and during pregnancy are associated with an increased risk of adverse pregnancy outcomes and fetal adverse effects. To reduce the risk of hyperphenylalaninemia-induced fetal adverse effects, blood phenylalanine concentrations should be maintained between 120 and 360 micromol/L during pregnancy and during the 3 months before conception. Data Human Data Uncontrolled Maternal PKU Available data from the Maternal Phenylketonuria Collaborative Study on 468 pregnancies and 331 live births in PKU-affected women demonstrated that uncontrolled Phe levels above 600 micromol/L are associated with a very high incidence of neurological, cardiac, facial dysmorphism, and growth anomalies.

Control of blood phenylalanine during pregnancy is essential to reduce the incidence of Phe-induced teratogenic effects. Animal Data No effects on embryo-fetal development were observed in a reproduction study in rats using oral doses of up to 400 mg/kg per day sapropterin dihydrochloride (about 3 times the MRHD of 20 mg/kg per day, based on body surface area) administered during the period of organogenesis. However, in a rabbit reproduction study, oral administration of a maximum dose of 600 mg/kg per day (about 10 times the MRHD, based on body surface area) during the period of organogenesis was associated with a non-statistically significant increase in the incidence of holoprosencephaly in two high dose-treated litters (4 fetuses), compared to one control-treated litter (1 fetus).

Pediatric Use Pediatric patients with PKU, ages 1 month to 16 years, have been treated with sapropterin dihydrochloride in clinical trials. The efficacy and safety of sapropterin dihydrochloride have not been established in neonates. The safety of sapropterin dihydrochloride has been established in children younger than 4 years in trials of 6 months duration and in children 4 years and older in trials of up to 3 years in length.

In children aged 1 month and older, the efficacy of sapropterin dihydrochloride has been demonstrated in trials of 6 weeks or less in duration . In a multicenter, open-label, single arm study, 57 patients aged 1 month to 6 years who were defined as sapropterin dihydrochloride responders after 4 weeks of sapropterin dihydrochloride treatment and Phe dietary restriction were treated for 6 months with sapropterin dihydrochloride at 20 mg/kg per day. The effectiveness of sapropterin dihydrochloride alone on reduction of blood Phe levels beyond 4 weeks could not be determined due to concurrent changes in dietary Phe intake during the study. Mean (±SD) blood Phe values over time for patients aged 1 month to <2 years and 2 to <7 years are shown in Figure 1. fig1

Two unintentional overdosages with sapropterin dihydrochloride have been reported. One adult patient in a sapropterin dihydrochloride clinical trial received a single sapropterin dihydrochloride dose of 4,500 mg (36 mg/kg) instead of 2,600 mg (20 mg/kg). The patient reported mild headache and mild dizziness immediately after taking the dose; both symptoms resolved within 1 hour with no treatment intervention. There were no associated laboratory test abnormalities.

The patient suspended therapy for 24 hours and then restarted sapropterin dihydrochloride with no reports of abnormal signs or symptoms. In postmarketing, one pediatric patient received sapropterin dihydrochloride doses of 45 mg/kg per day instead of 20 mg/kg per day. The patient reported hyperactivity that began at an unspecified time after overdosage and resolved after the sapropterin dihydrochloride dose was reduced to 20 mg/kg per day.

In a clinical study to evaluate the effects of sapropterin dihydrochloride on cardiac repolarization, a single supra-therapeutic dose of 100 mg/kg (5 times the maximum recommended dose) was administered to 54 healthy adults. No serious adverse reactions were reported during the study. The only adverse reactions reported in more than 1 subject who received the supra-therapeutic dose were upper abdominal pain (6%) and dizziness (4%). A dose-dependent shortening of the QT interval was observed.

Patients should be advised to notify their physicians in cases of overdosage.